bHLH class transcription factors take centre stage in phytochrome signalling.

The phytochrome family of photoreceptors (there are five phytochromes in Arabidopsis, named phyA to phyE) maximally absorbs red and far-red light and plays important functions throughout the life cycle of plants. Several recent studies have shown that multiple related bHLH (basic helix-loop-helix) class transcription factors play key roles in phytochrome signal transduction. Somewhat surprisingly these transcription factors primarily act as negative regulators of phytochrome signalling. Moreover, in some cases, the phytochromes inhibit those negative regulators.

Stimulus-induced, sleep-bound, focal seizures: a case report.

STUDY OBJECTIVES: In nocturnal frontal lobe epilepsy (NFLE), seizures occur almost exclusively during NREM sleep. Why precisely these seizures are sleep-bound remains unknown. Studies of patients with nonlesional familial forms of NFLE have suggested the arousal system may play a major role in their pathogenesis. We report the case of a patient with pharmaco-resistant, probably cryptogenic form of non-familial NFLE and strictly sleep-bound seizures that could be elicited by alerting stimuli and were associated with ictal bilateral thalamic and right orbital-insular hyperperfusion on SPECT imaging. DESIGN: Case report. SETTING: University Hospital Zurich. PATIENTS OR PARTICIPANTS: One patient with pharmaco-resistant epilepsy. CONCLUSION: This case shows that the arousal system plays a fundamental role also in cryptogenic non-familial forms of NFLE.

The effects of gamma-hydroxybutyrate, baclofen and GABAB receptors on brain activity and sleep in mice and humans

Currently, there is an increased interest in γ-hydroxybutyric acid (GHB) and its effects onsleep. This compound, sometimes referred to as 'rape drug', was recently approved as atreatment for the sleep disorder narcolepsy. Although several studies suggest that GHBinduces slow-wave sleep duration and improves sleep quality by increasing EEG slow-waveactivity, others question its ability to induce physiological sleep. GHB's mechanism of actionis still unclear, although in vivo and in vitro it seems to act at high doses as a low-affinityagonist of GABAB receptors. Furthermore, the role GABAB receptors play in sleep and theelectroencephalogram (EEG) is largely unknown.The aim of this project was therefore to investigate the effects of GHB on sleep and EEG, theinvolvement of GABAB receptors in mediating these effects, as well as the intrinsic role ofeach GABAB receptor subunit in the regulation of sleep. Thus, we administered GHB andbaclofen (BAC, a high-affinity agonist at GABAB receptor) to mice lacking the different GABABreceptor subunits and to healthy human volunteers.Our results, both in mice and humans, showed that GHB produced slow waves exclusivelythrough the stimulation of GABAB receptors, but did not induce physiological sleepnecessary to reduce sleep need and to increase cognitive performance. Unlike GHB, BACaffected the homeostatic regulation of sleep (sleep need) and induced a delayedhypersomnia. Finally, GABAB receptor and its subunits seem to play an important role insleep and in particular its circadian distribution.

Five years of sleep apnea treatment with a mandibular advancement device. Side effects and technical complications

Objective: To determine the variation in prevalence of temporomandibular disorders (TMD), other side effects, and technical complications during 5 years of sleep apnea treatment with a mandibular advancement device. Materials and Methods: Forty patients diagnosed with obstructive sleep apnea received an adjustable appliance at 70% of the maximum protrusion. The protrusion was then progressively increased. TMD (diagnosed according to the Research Diagnostic Criteria for TMD), overjet, overbite, occlusal contacts, subjective side effects, and technical complications were recorded before and a mean of 14, 21, and 58 months after treatment and analyzed by the Wilcoxon test (P Less-than .05). Results: Fifteen patients still used the oral appliance at the 5-year follow-up, and no significant variation in TMD prevalence was observed. Subjective side effects were common, and a significant reduction was found in overjet, overbite, and in the number of occlusal contacts. Furthermore, the patients made a mean of 2.5 unscheduled dental visits per year and a mean of 0.8 appliance repairs/relines per year by a dental technician. The most frequent unscheduled visits were needed during the first year and were a result of acrylic breakage on the lateral telescopic attachment, poor retention, and other adjustments to improve comfort. Conclusions: Five-year oral appliance treatment does not affect TMD prevalence but is associated with permanent occlusal changes in most sleep apnea patients during the first 2 years. Patients seek several unscheduled visits, mainly because of technical complications.

Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.

BACKGROUND: Stage IIIB non-small-cell lung cancer (NSCLC) is usually thought to be unresectable, and is managed with chemotherapy with or without radiotherapy. However, selected patients might benefit from surgical resection after neoadjuvant chemotherapy and radiotherapy. The aim of this multicentre, phase II trial was to assess the efficacy and toxicity of a neoadjuvant chemotherapy and radiotherapy followed by surgery in patients with technically operable stage IIIB NSCLC. METHODS: Between September, 2001, and May, 2006, patients with pathologically proven and technically resectable stage IIIB NSCLC were sequentially treated with three cycles of neoadjuvant chemotherapy (cisplatin with docetaxel), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and definitive surgery. The primary endpoint was event-free survival at 12 months. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030810. FINDINGS: 46 patients were enrolled, with a median age of 60 years (range 28-70). 13 (28%) patients had N3 disease, 36 (78%) had T4 disease. All patients received chemotherapy; 35 (76%) patients received radiotherapy. The main toxicities during chemotherapy were neutropenia (25 patients [54%] at grade 3 or 4) and febrile neutropenia (nine [20%]); the main toxicity after radiotherapy was oesophagitis (ten patients [29%]; nine grade 2, one grade 3). 35 patients (76%) underwent surgery, with pneumonectomy in 17 patients. A complete (R0) resection was achieved in 27 patients. Peri-operative complications occurred in 14 patients, including two deaths (30-day mortality 5.7%). Seven patients required a second surgical intervention. Pathological mediastinal downstaging was seen in 11 of the 28 patients who had lymph-node involvement at enrolment, a complete pathological response was seen in six patients. Event-free survival at 12 months was 54% (95% CI 39-67). After a median follow-up of 58 months, the median overall survival was 29 months (95% CI 16.1-NA), with survival at 1, 3, and 5 years of 67% (95% CI 52-79), 47% (32-61), and 40% (24-55). INTERPRETATION: A treatment strategy of neoadjuvant chemotherapy and radiotherapy followed by surgery is feasible in selected patients. Toxicity is considerable, but manageable. Survival compares favourably with historical results of combined treatment for less advanced stage IIIA disease. FUNDING: Swiss Group for Clinical Cancer Research (SAKK) and an unrestricted educational grant by Sanofi-Aventis (Switzerland).

Prospective randomized study of two cryopreservation policies avoiding embryo selection: the pronucleate stage leads to a higher cumulative delivery rate than the early cleavage stage.

OBJECTIVE: To compare the cumulative live birth rates obtained after cryopreservation of either pronucleate (PN) zygotes or early-cleavage (EC) embryos. DESIGN: Prospective randomized study. SETTING: University hospital. PATIENT(S): Three hundred eighty-two patients, involved in an IVF/ICSI program from January 1993 to December 1995, who had their supernumerary embryos cryopreserved either at the PN (group I) or EC (group II) stage. For 89 patients, cryopreservation of EC embryos was canceled because of poor embryo development (group III). Frozen-thawed embryo transfers performed up to December 1998 were considered. MAIN OUTCOME MEASURE(S): Age, oocytes, zygotes, cryopreserved and transferred embryos, damage after thawing, cumulative embryo scores, implantation, and cumulative live birth rates. RESULT(S): The clinical pregnancy and live birth rates were similar in all groups after fresh embryo transfers. Significantly higher implantation (10.5% vs. 5.9%) and pregnancy rates (19.5% vs. 10.9%; P< or = .02 per transfer after cryopreserved embryo transfers were obtained in group I versus group II, leading to higher cumulative pregnancy (55.5% vs. 38.6%; P < or = .002 and live birth rates (46.9% vs. 27.7%; P< or = .0001.Conclusion(s): The transfer of a maximum of three unselected embryos and freezing of all supernumerary PN zygotes can be safely done with significantly higher cumulative pregnancy chances than cryopreserving at a later EC stage.

Planning sleep-related animal and translational research

With the aim of improving human health, scientists have been using an approach referred to as translational research, in which they aim to convey their laboratory discoveries into clinical applications to help prevent and cure disease. Such discoveries often arise from cellular, molecular, and physiological studies that progress to the clinical level. Most of the translational work is done using animal models that share common genes, molecular pathways, or phenotypes with humans. In this article, we discuss how translational work is carried out in various animal models and illustrate its relevance for human sleep research and sleep-related disorders.

Influence of CD4+/CD25+ regulatory T cells on atherogenesis in patients with end-stage kidney disease.

Atherosclerosis, which is influenced by both traditional and nontraditional cardiovascular risk factors and has been characterized as an inflammatory process, is considered to be the main cause of the elevated cardiovascular risk associated with chronic kidney disease. The inflammatory component of atherosclerosis can be separated into an innate immune response involving monocytes and macrophages that respond to the excessive uptake of lipoproteins and an adaptive immune response that involves antigen-specific T cells. Concurrent with the influx of immune cells to the site of atherosclerotic lesion, the role of the adaptive immune response gradually increases. One of those cells are represented by the CD4+/CD25+ Tregs, which play indispensable roles in the maintenance of natural self-tolerance and negative control of pathological, as well as physiological, immune responses. Altered self-antigens such as oxidized LDLs may induce the development of CD4+/CD25+ Tregs with atheroprotective properties. However, atherosclerosis may be promoted by an imbalance between regulatory and pathogenic immunity that may be represented by the low expression of the forkhead box transcription factor (Foxp3) in CD4+/CD25+ Tregs. Such a defect may break immunologic tolerance and alter both specific and bystander immune suppression, leading to exacerbation of plaque development. Patients with end-stage kidney disease (ESKD) display a cellular immune dysfunction and accelerated atherosclerosis. Uremic solutes that accumulate during ESKD may be involved in these processes. In patients with ESKD and especially in those that are chronically hemodialyzed, oxidative stress induced by oxidized LDLs may increase CD4+/CD25+ Treg sensitivity to Fas-mediated apoptosis as a consequence of specific dysregulation of IL-2 expression. This review will focus on the current state of knowledge regarding the influence of CD4+/CD25+ Tregs on atherogenesis in patients with ESKD, and the potential effect of statins on the circulating number and the functional properties of these cells.

Protection against Plasmodium falciparum challenge induced in Aotus monkeys by liver-stage antigen-3-derived long synthetic peptides.

The vaccine potential of Plasmodium falciparum liver stage antigen-3 (LSA3) was investigated in Aotus monkeys using two long synthetic peptides corresponding respectively to an N-terminal non-repeat peptide (NRP) and repeat 2 (R2) region of the LSA3, adjuvanted by ASO2. Both 100-222 (NRP) and 501-596 repeat peptides induced effector B- and T-cell responses in terms of antigen-driven antibodies and/or specific IFN-gamma secretion. Animals challenged with P. falciparum sporozoites were protected following immunization with either the NRP region alone or the NRP combined with the R2 repeat region, as compared with controls receiving the adjuvant alone. These results indicate that the NRP may be sufficient to induce full, sterile protection and confirm the vaccine potential of LSA3 previously demonstrated in chimpanzees and in Aotus.

Emergence, longevity and fecundity of Trissolcus basalis and Telenomus podisi after cold storage in the pupal stage

Pupae of Trissolcus basalis (Wollaston) and Telenomus podisi Ashmead (Hymenoptera: Scelionidae) were stored at 12ºC and 15ºC for 120-210 days, after different periods of parasitism at 18ºC in order to evaluate adult emergence, longevity and ovipositional capacity. There was no emergence of adults at 12ºC. The rate of emergence of parasitoids transferred to 15ºC at the beginning of the pupal stage was 1.5% and 26.3%, for T. basalis and T. podisi respectively, whereas those parasitoids transferred one day before the expected date of emergence at 18ºC showed 86.4% of emergence for T. basalis and 59.9% for T. podisi. Mean adult longevity was also significantly lower when pupae were transferred to 15ºC at the beginning of the pupal stage. Females emerged after storage and maintained for 120 to 210 days at 15ºC parasitized host eggs after transference to 25ºC; however, fecundity of T. podisi was reduced in about 80% after cold storage.

Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis.

OBJECTIVE: To assess health-related quality of life (HRQOL) in abatacept-treated children/adolescents with juvenile idiopathic arthritis (JIA). METHODS: In this phase III, double-blind, placebo-controlled trial, subjects with active polyarticular course JIA and an inadequate response/intolerance to ≥1 disease-modifying antirheumatic drug (including biologics) received abatacept 10 mg/kg plus methotrexate (MTX) during the 4-month open-label period (period A). Subjects achieving the American College of Rheumatology Pediatric 30 criteria for improvement (defined "responders") were randomized to abatacept or placebo (plus MTX) in the 6-month double-blind withdrawal period (period B). HRQOL assessments included 15 Child Health Questionnaire (CHQ) health concepts plus the physical (PhS) and psychosocial summary scores (PsS), pain (100-mm visual analog scale), the Children's Sleep Habits Questionnaire, and a daily activity participation questionnaire. RESULTS: A total of 190 subjects from period A and 122 from period B were eligible for analysis. In period A, there were substantial improvements across all of the CHQ domains (greatest improvement was in pain/discomfort) and the PhS (8.3 units) and PsS (4.3 units) with abatacept. At the end of period B, abatacept-treated subjects had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement patterns were seen with pain and sleep. For participation in daily activities, an additional 2.6 school days/month and 2.3 parents' usual activity days/month were gained in period A responders with abatacept, and further gains were made in period B (1.9 versus 0.9 [P = 0.033] and 0.2 versus -1.3 [P = 0.109] school days/month and parents' usual activity days/month, respectively, in abatacept- versus placebo-treated subjects). CONCLUSION: Improvements in HRQOL were observed with abatacept, providing real-life tangible benefits to children with JIA and their parents/caregivers.